Understanding complexity in the HIF signaling pathway using systems biology and mathematical modeling

Hypoxia is a common micro-environmental stress which is experienced by cells during a range of physiologic and pathophysiologic processes. The identification of the hypoxia-inducible factor (HIF) as the master regulator of the transcriptional response to hypoxia transformed our understanding of the mechanism underpinning the hypoxic response at the molecular level and identified HIF as a potentially important new therapeutic target. It has recently become clear that multiple levels of regulatory control exert influence on the HIF pathway giving the response a complex and dynamic activity profile. These include positive and negative feedback loops within the HIF pathway as well as multiple levels of crosstalk with other signaling pathways. The emerging model reflects a multi-level regulatory network that affects multiple aspects of the physiologic response to hypoxia including proliferation, apoptosis, and differentiation. Understanding the interplay between the molecular mechanisms involved in the dynamic regulation of the HIF pathway at a systems level is critically important in defining new appropriate therapeutic targets for human diseases including ischemia, cancer, and chronic inflammation. Here, we review our current knowledge of the regulatory circuits which exert influence over the HIF response and give examples of in silico model-based predictions of the dynamic behaviour of this system

Determinants of synaptic integration and heterogeneity in rebound firing explored with data-driven models of deep cerebellar nucleus cells

Significant inroads have been made to understand cerebellar cortical processing but neural coding at the output stage of the cerebellum in the deep cerebellar nuclei (DCN) remains poorly understood. The DCN are unlikely to just present a relay nucleus because Purkinje cell inhibition has to be turned into an excitatory output signal, and DCN neurons exhibit complex intrinsic properties. In particular, DCN neurons exhibit a range of rebound spiking properties following hyperpolarizing current injection, raising the question how this could contribute to signal processing in behaving animals. Computer modeling presents an ideal tool to investigate how intrinsic voltage-gated conductances in DCN neurons could generate the heterogeneous firing behavior observed, and what input conditions could result in rebound responses. To enable such an investigation we built a compartmental DCN neuron model with a full dendritic morphology and appropriate active conductances. We generated a good match of our simulations with DCN current clamp data we recorded in acute slices, including the heterogeneity in the rebound responses. We then examined how inhibitory and excitatory synaptic input interacted with these intrinsic conductances to control DCN firing. We found that the output spiking of the model reflected the ongoing balance of excitatory and inhibitory input rates and that changing the level of inhibition performed an additive operation. Rebound firing following strong Purkinje cell input bursts was also possible, but only if the chloride reversal potential was more negative than −70 mV to allow de-inactivation of rebound currents. Fast rebound bursts due to T-type calcium current and slow rebounds due to persistent sodium current could be differentially regulated by synaptic input, and the pattern of these rebounds was further influenced by HCN current. Our findings suggest that active properties of DCN neurons could play a crucial role for signal processing in the cerebellum

Three pillars of sustainability: in search of conceptual origins

The three-pillar conception of (social, economic and environmental) sustainability, commonly represented by three intersecting circles with overall sustainability at the centre, has become ubiquitous. With a view of identifying the genesis and theoretical foundations of this conception, this paper reviews and discusses relevant historical sustainability literature. From this we find that there is no single point of origin of this three-pillar conception, but rather a gradual emergence from various critiques in the early academic literature of the economic status quo from both social and ecological perspectives on the one hand, and the quest to reconcile economic growth as a solution to social and ecological problems on the part of the United Nations on the other. The popular three circles diagram appears to have been first presented by Barbier (Environ Conserv 14:101, doi: 10.1017/s0376892900011449, 1987), albeit purposed towards developing nations with foci which differ from modern interpretations. The conceptualisation of three pillars seems to predate this, however. Nowhere have we found a theoretically rigorous description of the three pillars. This is thought to be in part due to the nature of the sustainability discourse arising from broadly different schools of thought historically. The absence of such a theoretically solid conception frustrates approaches towards a theoretically rigorous operationalisation of ‘sustainability’

Airborne trace elements near a petrochemical industrial complex in Thailand assessed by the lichen Parmotrema tinctorum (Despr. ex Nyl.) Hale

7siSeveral trace elements discharged by the petrochemical industry are toxic to humans and the ecosystem. In this study, we assessed airborne trace elements in the vicinity of the Map Ta Phut petrochemical industrial complex in Thailand by transplanting the lichen Parmotrema tinctorum to eight industrial, two rural, and one clean air sites between October 2013 and June 2014. After 242 days, the concentrations of As, Cd, Co, Cr, Cu, Hg, Mo, Ni, Pb, Sb, Ti, V, and Zn in lichens at most industrial sites were higher than those at the rural and the control sites; in particular, As, Cu, Mo, Sb, V, and Zn were significantly higher than at the control site (p < 0.05). Contamination factors (CFs) indicated that Cd, Cu, Mo, and Sb, which have severe health impacts, heavily contaminated at most industrial sites. Principal component analysis (PCA) showed that most elements were associated with industry, with lesser contributions from traffic and agriculture. Based on the pollution load indexes (PLIs), two industrial sites were highly polluted, five were moderately polluted, and one had a low pollution level, whereas the pollution load at the rural sites was comparable to background levels. This study reinforces the utility of lichens as cost-effective biomonitors of airborne elements, suitable for use in developing countries, where adequate numbers of air monitoring instruments are unavailable due to financial, technical, and policy constraints.partially_openopenBoonpeng, Chaiwat; Polyiam, Wetchasart; Sriviboon, Chutima; Sangiamdee, Duangkamon; Watthana, Santi; Nimis, Pier Luigi; Boonpragob, KansriBoonpeng, Chaiwat; Polyiam, Wetchasart; Sriviboon, Chutima; Sangiamdee, Duangkamon; Watthana, Santi; Nimis, Pierluigi; Boonpragob, Kansr